The ability of a compound to exist in different crystal structures is known as polymorphism. These different crystalline forms are known as “polymorphic modifications” or “polymorphs.” While polymorphs have the same chemical composition, they differ in packing and geometrical arrangement and exhibit different physical properties such as melting point, shape, color, density, hardness, deformability, stability, dissolution and the like (Theory and Origin of Polymorphism in “Polymorphism in Pharmaceutical Solids” (1999) ISBN: 0-8247-0237).
Valomaciclovir [L-valine, (3R)-3-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methyl]-4-[(1-oxooctadecyl)oxy]butyl ester], also known by the USAN as valomaciclovir stearate or the proprietary codes EPB-348, MIV-606 or RP-606 (FIG. 1A), is the diester prodrug (valine and stearic acid) of the acyclic guanosine derivative H2G (FIG. 1B), a potent, broad-spectrum anti-herpes agent. H2G has potent activity against human varicella zoster virus (VZV), Epstein-Barr virus (EBV), human herpesvirus-6 (HHV-6), HSV-I, and HSV-2. U.S. Pat. No. 5,869,493 describes the preparation and activity of valomaciclovir.
Valomaciclovir has been under development as an orally active agent against shingles (zoster) and other viral diseases. Valomaciclovir was safe and well tolerated after multiple dosing with total daily doses of up to 6.0 g as shown in several phase I human clinical studies. Results from a phase II study (M98-829) using a suspension of valomaciclovir at 250, 500, and 750 mg administered BID for 7 days to zoster patients, with acyclovir as a control, provided proof-of-concept for zoster lesion healing and a basis for further use of valomaciclovir in patients with post-herpetic neuralgia.
Valomaciclovir includes a guanine moiety, an amino acid ester and a long chain fatty acid ester. Each of these components has been associated with various formulation difficulties, and valomaciclovir is no exception. Published patent applications (e.g., International Publications Nos. WO98/34917, WO00/08025 and WO03/02564) and U.S. Pat. No. 6,184,376 describe various synthetic routes for valomaciclovir. However, these prior art synthetic routes tended to produce amorphous materials, mixtures of amorphous and crystalline material or mixtures of poorly characterized partially ordered materials. The resulting material often suffered from extremely poor flowability and agglomeration, significantly hampering handling and processing. Previous phase I and phase II clinical trials with valomaciclovir employed liquid suspensions that avoided the difficulties in handling and processing because of the physical nature of the material. However, liquid suspensions are not a clinically preferred formulation, because they are not easy to administer, especially to elderly patients who are the main patient population for a shingles medication.
Accordingly, there remains a need for stable crystalline forms of valomaciclovir and reproducible processes for producing these stable forms.